Less severe to moderate headaches (e.g., tension headaches) are experienced by about seventy five percent of Americans, while more than forty percent of Americans experience six or more less severe to moderate headaches per year. Approximately twenty percent of people suffer at least one severe headache per year, and in North America alone 28 million people have been diagnosed with recurring migraines. Severe headaches often limit a person significantly in their ability to engage in life, and it is estimated that approximately 157 million working days per year are lost due to headaches.
It is generally believed that vascular headaches and particularly migraine are at least in part caused by swelling of blood vessels in the scalp, in the meninges (i.e., pia mater, dura mater, and arachnoid membrane), and/or in the brain itself. Both scalp and meninges are innervated by pain fibers, onto which the swollen vessels are thought to press. The swelling of the blood vessels can be triggered by a variety of factors, including intrinsic factors (e.g., stress), and/or extrinsic factors. For example, caffeine acts as a vasoconstrictive agent in the brain, and consequently many people experience headaches upon caffeine withdrawal.
There are various pharmacological treatments known in the art to reduce headaches. For example, many people use Aspirin™ (Acetylic salicylic acid) or Tylenol™ (Acetaminophen) to reduce their headache. Although such over-the-counter drugs are often relatively effective to at least reduce some of the pain, they tend to incur, and especially in higher dosages and/or prolonged administration, significant side effects (e.g., ulcers, increase in coagulation time, etc.).
In alternative treatments, pharmacologically active agents are systemically administered to target receptors that are functionally involved in vasoconstriction of blood vessels in the cerebral circulation, thereby relieving the pressure perceived as a headache. Examples for such pharmacologically active agents include triptans (e.g., Sumatriptan and Rizatriptan), and various ergots that target the 5HT receptors, which stimulate cerebral vasoconstriction [Hargreaves in Cephalalgia (2000) 20 Suppl 1:2-9].
In a still further example, caffeine and other methylxanthines (although vasodilating in the periphery) stimulate vasoconstriction in the cerebral circulation. Such methylxanthines are probably effective by stimulation of the release of endogenous epinephrine and norepinephrine, both of which are potent cerebral vasoconstrictors [Muller-Schweinitzer and Fanchamps in Adv. Neurol. (1982) 33:343-356]. Caffeine is a component of several over-the-counter migraine and headache medications. However, in known formulations caffeine needs to be orally ingested in substantial quantities to reduce a headache, which often produces undesirable side effects (e.g., excessive central nervous stimulation).
Although there are various methods and compositions known in the art to reduce headache and/or migraine, all or almost all of them suffer from one or more disadvantage. Therefore, there is still a need to provide improved methods and compositions for treatment of headache and/or migraine.